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NORD gratefully acknowledges Victoria Werth, MD, Member, International Pemphigus and Pemphigoid Foundation (IPPF) Medical Advisory Council; Chief, Dermatology, Philadelphia V.A. Hospital; Professor of Medicine and Professor of Dermatology at the Hospital of the University of Pennsylvania and the Veteran’s Administration Medical Center, for assistance in the preparation of this report.
Pemphigus and pemphigoid are rare autoimmune blistering diseases of the skin and/or mucous membranes. Pemphigus affects the outer layer of the skin (epidermis) and causes lesions and blisters that easily rupture. Pemphigoid affects a lower layer of the skin, between the epidermis and the dermis, creating tense blisters that do not break easily. Sometimes pemphigoid may look like hives or eczema without blisters.
The term “pemphigus” is used in a very specific way to describe blistering disorders caused by autoantibodies such as desmoglein 1 and desmoglein 3 that recognize components of the epidermis and lead to disruption of the intercellular junctions, loss of integrity and formation of blisters.
Pemphigoid is a group of subepidermal, blistering autoimmune diseases that primarily affect the skin, especially in the lower abdomen, groin and flexor surfaces of the extremities. Here, autoantibodies (anti-BPA-2 and anti-BPA-1) are directed against the basal layer of the epidermis and mucosa.
The patient’s immune system makes antibodies, which attack viruses and harmful bacteria. In the context of pemphigus and pemphigoid, the immune system is over-active, and antibodies instead attack healthy cells in the skin or mucous membranes. As a result, skin cells separate from each other, fluid collects between skin layers and blisters form and may cover a large area of skin.
There are several different types of pemphigus.
Pemphigus Vulgaris (PV)
PV is the most common of these conditions. Blisters are soft and fragile and may form at the mouth first and then spread to the skin and even the genitals. Blisters are frequently painful but not itchy, and in the mouth make chewing and swallowing difficult. PV does not cause permanent scarring unless there is an infection associated with the sore.
Pemphigus Foliaceus (PF)
PF is a less severe type. Blisters may form on the scalp and face first and then spread to the chest and back. Blisters do not occur in the mouth. Blisters are not usually painful and are superficial and form crusts.
This type results in thicker sores, mainly in the groin and under the arms.
This type is caused by the IgA antibody binding to epidermal cell proteins. It may resemble pemphigus foliaceus or may appear as small pustules.
Paraneoplastic Pemphigus (PNP)
PNP is associated with certain forms of cancer. Blisters form inside the mouth and may affect the lungs, leading to a fatal outcome. Sores of the mouth, lips and esophagus are almost always present and skin lesions of different types occur. PNP can affect the lungs. In some patients, the diagnosis will prompt doctors to search for a hidden tumor. In some patients, the tumor will be benign, and the disease will improve if the tumor is surgically removed.
Mucous Membrane Pemphigoid (MMP)
MMP affects the eyes, mouth and throat. A clinical form called ocular cicatricial pemphigoid (OCP) can result in blindness if it involves the eyes and respiratory compromise if it involves the deeper parts of the throat.
Bullous Pemphigoid (BP)
BP is frequently limited to the skin with blisters presenting predominantly on the abdomen, groin, back, arms and legs. The blisters may itch and be painful.
Gestational Pemphigoid (GP)
GP is characterized by a blistering rash starting around the navel and spreading to the entire body, typically in the second or third trimester of pregnancy.
Epidermolysis Bullosa Acquisita (EBA)
EBA involves a blistering rash on the skin and/or mucosal surfaces. Blisters are usually smaller than in pemphigoid.
Pemphigus and pemphigoid are not inherited but there can be a genetic predisposition to develop the disease. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental factors. It is not currently possible to predict who may get these diseases.
Males and females are equally affected. The conditions are known to affect people from all racial and cultural backgrounds. However, there are certain groups of people (Ashkenazi Jews, people of Mediterranean, North Indian and Persian decent) who have a higher incidence of pemphigus.
Pemphigus and pemphigoid are diagnosed through special testing and clinical presentation. Types of testing include:
Lesion biopsy — a sample of skin is removed by biopsy and examined under the microscope. Additionally, the layer of skin in which cell-to-cell separation occurs can be determined.
Direct immunofluorescence — the skin sample is treated to detect desmoglein autoantibodies in the skin. The presence of these antibodies indicates pemphigus. In pemphigoid and other basement membrane autoimmune blistering diseases, other autoantibodies can be detected.
Indirect immunofluorescence or antibody titer test — this measures desmoglein autoantibodies in the blood serum in pemphigus. In bullous pemphigoid BP180 and BP230 antibodies can be measured in the serum. Anti-type VII collagen is found in EBA. It may be used to obtain a more complete understanding of the course of the disease.
There is currently no cure for pemphigus or pemphigoid, but these conditions can usually be controlled. A decrease in or disappearance of signs and symptoms (remission) is possible. The treatment of pemphigus and pemphigoid is directed toward suppressing the skin and mucosal lesions of the disease and preventing complications potentially associated with its treatment. Most patients will eventually enter a complete remission in which they are off all therapy and there is no evidence of the disease. Generally, the less widespread the pemphigus is, the easier it is to control. The development, severity and progression of the diseases are not uniform and the response to therapies can vary among individuals. Consequently, physicians will take several different factors into account when planning an individual’s treatment, which will be tailored to the individual’s specific needs and situation.
Treatment is usually separated into phases: control, consolidation and maintenance. In the control phase, high-intensity therapy is used to bring the disorder under control by initiating the clearance of current lesions, reducing or suppressing new lesion formation, and improving other symptoms such as itch relief. In the consolidation phase, a consistent dose of medication is used until a significant portion of lesions have healed. In the maintenance phase, the dose of medication is gradually reduced until a minimal level is achieved that is successful in preventing the development of new lesions.
The mainstay of treatment is the use of corticosteroids such as prednisone, which are anti-inflammatory medications that also suppress the normal function of the immune system. Steroids may be applied directly to the affected areas (topically) or may be taken by mouth or given by injection (systemic steroids). Topical therapy is generally given to reduce pain and prevent or treat infection. Most individuals will receive systemic steroids to bring about control of pemphigus. The dose of steroids used can be tapered once control of the disorder is achieved.
Rituximab is now considered a first-line therapy for pemphigus, and it was recently approved by the FDA for this indication. Rituximab can prevent new autoantibodies from forming. It takes 3-4 months for the existing autoantibody levels to fall, during which time some dose of steroids may be required.
Other medications that may be used in combination with corticosteroids to treat individuals with pemphigus include drugs that suppress the immune system (immunosuppressive drugs) such as mycophenolate mofetil, azathioprine, methotrexate or cyclophosphamide; drugs that modify or regulate the immune system (immunomodulatory drugs) dapsone; or antibiotics such as doxycycline. These medications may be used to allow physicians to lower the overall dose of steroids. Some individuals respond to therapy quickly; others respond more slowly or do not respond at all. In severe cases or in cases where individuals fail to respond to other therapies, pulse steroids, plasmapheresis or intravenous immunoglobulin therapy (IVIG) may be used.
Research has indicated that IVIG therapy can markedly decrease levels of the abnormal antibodies associated with pemphigus without decreasing the levels of normal, healthy antibodies. IVIG is normally given with other therapy such as steroids and immunosuppressive drugs, to prevent rebound of disease as the therapy is tapered.
Pulse-steroid therapy refers to the administration of extremely high levels of steroids given for a short period of time. Plasmapheresis is a method for removing unwanted substances (e.g., autoantibodies) from the blood, and is not used as much now because of increased risk of infections. Blood is removed from the patient and blood cells are separated from plasma. The patient’s plasma is then replaced with other human plasma and the blood is transfused into the patient. These approaches are most frequently used now only if rituximab is not tolerated or is ineffective.
The conditions themselves are rarely fatal, and most deaths occur from infections of compromised tissues. If left untreated, these diseases may be fatal.
There are a number of ongoing trials for pemphigus, including an infused antibody against the FcRN receptor that increases the removal of autoantibodies, a mechanism likely involved with IVIG. Another approach is a selective Bruton’s tyrosine kinase inhibitor, which has effects on pathways critical for B cell activation and antibody induction, antibodies against complement, as well as antibody-mediated activation of other immune cells.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/info-clinical- trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.
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